Targeting aminoacid lipids

Abstract

The present invention is directed to carrier systems comprising ether-lipids conjugated to one or more bioactive ligands and exposed on the surface of the carrier system for use in targeted delivery and/or antigen display systems. Optionally one or more further bioactive agents may be encapsulated or embedded within or attached to or adsorbed onto the carrier system. The present invention is further directed to methods of their preparation and their uses in medical applications, such as targeted delivery of bioactive agents to specific tissues or cells and antigen display systems for the study, diagnosis, and treatment of traits, diseases and conditions that respond to said bioactive agents.

The invention claimed is: 
     
       1. A carrier system comprising a compound of formula I 
       
         
           
           
               
               
           
         
         wherein 
         Y represents O, N, S or a covalent bond, 
         S 1 , S 2 , S 3  represent independently of each other a covalent bond or a spacer group, 
         X 1 , X 2 , X 3  represent independently of each other H or a ligand group or any two of X 1 , X 2 , X 3  may together form a ligand group, wherein at least one of X 1 , X 2 , X 3  is a legumain targeting ligand group, 
         L is a group of formula (a) 
       
       
         
           
           
               
               
           
         
       
       wherein the dashed line represents the linkage to N,
 R 1  represents H or a group of formula —(CH 2 ) 2 —OR b1 , 
 R 1 ′ represents H or a group of formula —(CH 2 ) 2 —OR b2 , 
 R 2  represents H or a group of formula —CH 2 —OR c , 
 R 2 ′ represents H or a group of formula —OR d  or —CH 2 —OR d , 
 R 3  represents H or a group of formula —(CH 2 ) 2 —OR e  or —(CH 2 ) 3 —OR e , 
 R a , R b1 , R b2 , 
 R c , R d , R e  represent independently of each other a saturated or unsaturated, straight or branched hydrocarbon chain, 
 m is 1, 2 or 3,
 with the proviso that at least one of R 1 , R 1 ′, R 2 , R 2 ′, R 3  is not H, 
 and 
 wherein at least one of the following conditions is satisfied:
 the carrier system comprises a pharmaceutically active agent in a solvated form; 
 or 
 the carrier system comprises one or more pteroyl derivatives and/or aza-peptide derivatives; 
 or 
 the carrier system has been lyophilized or freeze-dried and therefore has enhanced stability; 
 or 
 wherein at least one of X 1 , X 2 , X 3  is a ligand that is capable of binding to an antibody, antibody fragment, engineered antibody or an antibody mimic. 
 
 
 
     
     
       2. The carrier system according to  claim 1 , which comprises a pharmaceutically active agent in a solvated form. 
     
     
       3. The carrier system according to  claim 1 , which comprises one or more pteroyl derivatives and/or aza-peptide derivatives. 
     
     
       4. The carrier system according to  claim 1 , which has been lyophilized or freeze-dried and therefore has enhanced stability. 
     
     
       5. The carrier system according to  claim 1 , wherein at least one of X 1 , X 2 , X 3  is a ligand that is capable of binding to an antibody, antibody fragment, engineered antibody or an antibody mimic. 
     
     
       6. The carrier system according to  claim 1 , wherein R 3  is H, and L is a group of formulas (b) or (c) 
       
         
           
           
               
               
           
         
         wherein the dashed line represents the linkage to N, and 
         S 1 , S 2 , S 3 , X 1 , X 2 , X 3 , Y, R a , and m are defined as for formula I, 
         with the proviso that in formula (b) one of R 2  and R 2 ′ is not H, and in formula (c) one of R 1  and R 1 ′ is not H, and at least one of X 1 , X 2 , X 3  is a legumain targeting ligand group. 
       
     
     
       7. The carrier system according to  claim 6 , wherein L is a group of formula (b1), (b2), (b3) or (b4): 
       
         
           
           
               
               
           
         
         wherein the dashed line represents the linkage to N, and 
         wherein R a , R c  and R d  are independently of each other a saturated or unsaturated, straight or branched hydrocarbon chain. 
       
     
     
       8. The carrier system according to  claim 6 , wherein L is a group of formula (c1) or (c2): 
       
         
           
           
               
               
           
         
         wherein the dashed line represents the linkage to N, and 
         wherein R a , R b1 , R b2  are independently of each other a saturated or unsaturated, straight or branched hydrocarbon chain. 
       
     
     
       9. The carrier system according to  claim 1 , wherein R 1 , R 1 ′, R 2 , R 2 ′ are H, R 3  is a group of formula —(CH 2 ) 2 —OR e  or —(CH 2 ) 3 —OR e , and S 1 , S 2 , S 3 , X 1 , X 2 , X 3 , Y, R a , and m are defined as for formula I. 
     
     
       10. The carrier system according to  claim 1 , wherein R a , R b1 , R b2 , R c , R d , R e  are independently of each other straight or branched C(10-22)alkyl, C(10-22)alkenyl or C(10-22)alkynyl. 
     
     
       11. The carrier system according to  claim 10 , wherein C(10-22)alkenyl and C(10-22)alkynyl have 1, 2, 3 or 4 unsaturated bonds. 
     
     
       12. The carrier system according to  claim 10 , wherein C(10-22)alkenyl and C(10-22)alkynyl have 1 or 2 unsaturated bonds. 
     
     
       13. The carrier system according to  claim 1 , wherein the carrier system is a microparticulate or a nanoparticulate material. 
     
     
       14. The carrier system according to  claim 13 , wherein the microparticulate or a nanoparticulate material is a liposome or a micelle, comprising at least one compound of formula I and optionally one or more other co-lipids. 
     
     
       15. The carrier system according to  claim 13 , wherein the microparticulate or a nanoparticulate material is a lipid vesicle, a nanoparticle, a nanosphere and/or a nanorod, comprising at least one compound of formula I and optionally one or more other co-lipids. 
     
     
       16. The carrier system according to  claim 15 , wherein the lipid vesicle further contains at least one bioactive agent enclosed or embedded within its internal void or adsorbed onto or attached to its surface. 
     
     
       17. The carrier system according to  claim 1 , wherein the spacer group is polyethylene glycol or an end-capped polyethylene glycol. 
     
     
       18. The carrier system according to  claim 1 , wherein the at least one of X 1 , X 2 , X 3  that is a legumain targeting ligand group is RR11a. 
     
     
       19. The carrier system according to  claim 1 , wherein the carrier system is a liposome, and the at least one of X 1 , X 2 , X 3  that is a legumain targeting ligand group is RR11a. 
     
     
       20. The carrier system according to  claim 1 , wherein, in addition to at least one of X 1 , X 2 , X 3  being a legumain targeting ligand group, at least one further of X 1 , X 2 , X 3  or two of X 1 , X 2 , X 3  together is a targeting ligand or an antigenic ligand or a therapeutic or diagnostic ligand or a combination thereof. 
     
     
       21. A pharmaceutical composition comprising the carrier system according to  claim 1  and a pharmaceutically acceptable carrier. 
     
     
       22. A drug delivery system, diagnostic system or as an antigen display system, said system comprising the carrier system according to  claim 1  and a pharmaceutically acceptable carrier. 
     
     
       23. A method for the diagnosis of a disease by a disease specific diagnostic agent containing a legumain targeting ligand group, comprising administering to a host in need thereof a carrier system comprising a compound of formula I 
       
         
           
           
               
               
           
         
         wherein 
         Y represents O, N, S or a covalent bond, 
         S 1 , S 2 , S 3  represent independently of each other a covalent bond or a spacer group, 
         X 1 , X 2 , X 3  represent independently of each other H or a ligand group or any two of X 1 , X 2 , X 3  may together form a ligand group, wherein at least one of X 1 , X 2 , X 3  is a legumain targeting ligand group, 
         L is a group of formula (a) 
       
       
         
           
           
               
               
           
         
         
           wherein the dashed line represents the linkage to N, 
         
         R 1  represents H or a group of formula —(CH 2 ) 2 —OR b1 , 
         R 1′  represents H or a group of formula —(CH 2 ) 2 —OR b2 , 
         R 2  represents H or a group of formula —CH 2 —OR c , 
         R 2′  represents H or a group of formula —OR d  or —CH 2 —OR d , 
         R 3  represents H or a group of formula —(CH 2 ) 2 —OR e  or —(CH 2 ) 3 —OR e , 
         R a , R b1 , R b2 , R c , R d , R e  represent independently of each other a saturated or unsaturated, straight or branched hydrocarbon chain, 
         m is 1, 2 or 3,
 with the proviso that at least one of R 1 , R 1′ , R 2 , R 2′ , R 3  is not H, 
 wherein at least one of Xi, X 2 , X 3  is said diagnostic agent containing a legumain targeting ligand group; 
 or 
 a method for modulating an immune response, comprising administering to a host in need thereof the carrier system comprising the compound of formula I, wherein at least one of X 1 , X 2 , X 3  is an antigenic agent containing a legumain targeting ligand group; 
 or 
 a method for treating cancer, comprising administering to a subject in need thereof an effective amount of the carrier system comprising the compound of formula I, wherein said carrier system comprises a cancer therapeutic agent; 
 or 
 a method for treating an inflammatory disease, comprising administering to a subject in need thereof an effective amount of the carrier system comprising the compound of formula I, wherein said carrier system comprises an anti-inflammatory therapeutic agent; 
 or 
 a method for transporting a biologically active compound across a membrane and/or a method for delivering a biologically active compound into a cell, comprising achieving said transporting or delivery by the carrier system comprising the compound of formula I, which comprises said biologically active compound; 
 or 
 a method for eliciting a psychological response from a human patient, comprising administering to said human the carrier system comprising the compound of formula I, which comprises one or more bioactive agents; 
 or 
 a method for preventing a psychotic episode in a human subject, comprising administering to said human the carrier system comprising the compound of formula I, which comprises one or more antipsychotic agents; 
 or 
 a method for in vitro application for growth promotion and differentiation of cells or modification of expression profiles and post-translational modification patterns of biological products manufactured in a bioreactor, comprising administering into said bioreactor the carrier system comprising the compound of formula I, which bioreactor further contains said cells or biological products; 
 or 
 a method for preventing a disease in a human subject, comprising administering to said human the carrier system comprising the compound of formula I, which comprises one or more vaccines. 
 
       
     
     
       24. The method according to  claim 23 , which is for the diagnosis of a disease by a disease specific diagnostic agent containing a legumain targeting ligand group, comprising administering to a host in need thereof the carrier system comprising the compound of formula I, wherein at least one of X 1 , X 2 , X 3  is said diagnostic agent containing a legumain targeting ligand group. 
     
     
       25. The method according to  claim 23 , which is for modulating an immune response, comprising administering to a host in need thereof the carrier system comprising the compound of formula I, wherein at least one of X 1 , X 2 , X 3  is an antigenic agent containing a legumain targeting ligand group. 
     
     
       26. The method according to  claim 23 , which is for treating cancer, comprising administering to a subject in need thereof an effective amount of the carrier system comprising the compound of formula I, wherein said carrier system comprises a cancer therapeutic agent. 
     
     
       27. The method according to  claim 23 , which is for treating an inflammatory disease, comprising administering to a subject in need thereof an effective amount of the carrier system comprising the compound of formula I, wherein said carrier system comprises an anti-inflammatory therapeutic agent. 
     
     
       28. The method according to  claim 23 , which is for transporting a biologically active compound across a membrane and/or a method for delivering a biologically active compound into a cell, comprising achieving said transporting or delivery by the carrier system comprising the compound of formula I, which comprises said biologically active compound. 
     
     
       29. The method according to  claim 23 , which is for eliciting a psychological response from a human patient, comprising administering to said human the carrier system comprising the compound of formula I, which comprises one or more bioactive agents. 
     
     
       30. The method according to  claim 23 , which is for preventing a psychotic episode in a human subject, comprising administering to said human the carrier system comprising the compound of formula I, which comprises one or more antipsychotic agents. 
     
     
       31. The method according to  claim 23 , which is for in vitro application for growth promotion and differentiation of cells or modification of expression profiles and post-translational modification patterns of biological products manufactured in a bioreactor, comprising administering into said bioreactor the carrier system comprising the compound of formula I, which bioreactor further contains said cells or biological products. 
     
     
       32. The method according to  claim 23 , which is for preventing a disease in a human subject, comprising administering to said human the carrier system comprising the compound of formula I, which comprises one or more vaccines. 
     
     
       33. The method according to  claim 23 , wherein, in the compound of formula I, R 3  is H, and L is a group of formulas (b) or (c) 
       
         
           
           
               
               
           
         
         wherein the dashed line represents the linkage to N, and 
         S 1 , S 2 , S 3 , X 1 , X 2 , X 3 , Y, R a , and m are defined as for formula I, 
         with the proviso that in formula (b) one of R 2  and R 2 ′ is not H, and in formula (c) one of R 1  and R 1 ′ is not H, and at least one of X 1 , X 2 , X 3  is a legumain targeting ligand group. 
       
     
     
       34. The method according to  claim 23 , wherein, in the compound of formula I, L is a group of formula (b1), (b2), (b3) or (b4): 
       
         
           
           
               
               
           
         
         wherein the dashed line represents the linkage to N, and 
         wherein R a , R c  and R d  are independently of each other a saturated or unsaturated, straight or branched hydrocarbon chain;
 or 
 L is a group of formula (c1) or (c2): 
 
       
       
         
           
           
               
               
           
         
         wherein the dashed line represents the linkage to N, and 
         wherein R a , R b1 , R b2  are independently of each other a saturated or unsaturated, straight or branched hydrocarbon chain. 
       
     
     
       35. The method according to  claim 23 , wherein, in the compound of formula I,
 R 1 , R 1 ′, R 2 , R 2 ′ are H, R 3  is a group of formula —(CH 2 ) 2 —OR e  or —(CH 2 ) 3 —OR e , and S 1 , S 2 , S 3 , X 1 , X 2 , X 3 , Y, R a , and m are defined as for formula I; 
 and/or 
 R a , R b1 , R b2 , R c , R d , R e  are independently of each other straight or branched C(10-22)alkyl, C(10-22)alkenyl or C(10-22)alkynyl. 
 
     
     
       36. The method according to  claim 23 , wherein the carrier system has been lyophilized or freeze-dried and therefore has enhanced stability.